De-esterification process

ABSTRACT

An efficient process for de-esterification has been provided for by application of special tetrahalogenides. By applying this process a new compound, viz. cefesone, and especially the E-isomer thereof, has been prepared.

This application has an earlier U.S. Provisional Application No.60/007278 filed Nov. 6, 1995 this application is a 371 of PCT/EP96/04880filed Nov. 6, 1996.

TECHNICAL FIELD

The present invention relates to an improved method for esterhydrolysis. In particular, the invention relates to the deprotection ofcarboxyl esters by reaction with acidic metal halogenides (Lewis acids).

BACKGROUND AND RELEVANT LITERATURE

The protection and deprotection of carboxyl esters is an important partof many syntheses wherein carboxylate groups are involved. For instance,this protection and deprotection does often play a role in the synthesisof semi-synthetic cephalosporins (SSC's) and semi-synthetic penicillins(SSP's). SSC's are derivatized congeners of 7-aminocephalosporanic acid(7-ACA) or 7-aminodesacetoxycephalosporanic acid (7-ADCA) and salts andesters thereof; SSP's are derivatized congeners of 6-aminopenicillanicacid (6-APA).

In synthetic schemes leading to SSC's and SSP's a variety of protectinggroups is often employed. An important feature in protecting groupstrategy usually is blocking and deblocking of the carboxyl functionsince said carboxyl functions can undergo decarboxylation if leftunreacted (J. Amer. Chem. Soc. 1969, 91, 1401). Protection is achievedusing esterification with an alcohol that can be removed under acidic orneutral conditions. Important industrial examples of 4-carboxylprotecting groups are allyl, benzhydryl, benzyl, tert-butyl,4-methoxybenzyl, 4-nitrobenzyl and trichloroethyl. The known methods forremoval of protecting groups are either expensive (trifluoroaceticacid), difficult to process because of complexation (zinc/acetic acid),or suffer from low yields (hydrogenolysis in case of benzhydryl andbenzyl).

It is accordingly an object of the present invention to provide a newand improved process for converting carboxyl esters to the correspondingacid in high yield without the production of unwanted by-products.

It is also an object of the invention to provide new compounds by theapplication of this process, as for instance(6R,7R)-3-(2,4-dinitrostyryl)-7-phenylacetamido-ceph-3-em-4-carboxylicacid (cefesone), and the conversion in salts and esters thereof, and theE-isomers of the same. The chemical name of the racemic mixture hasrecently been indicated in J. Clin.. Micr. 1995, 1665, but a process toprepare the same has not been published up to now.

Aluminum trichloride-promoted hydrolysis of cephalosporin esters is aprocedure reported for the hydrolysis of benzyl esters (TetrahedronLett. 1979, 2793), benzhydryl esters (Pure & Appl. Chem. 1987, 59,1041), and 4-methoxybenzyl esters (Pure & Appl. Chem. 1989, 61, 325).

Surprisingly, it has been found that other Lewis acids, like telluriumtetrachloride, tin tetrachloride or titanium tetrachloride, can beapplied for the high yield hydrolysis of carboxyl esters, such astert-butyl and 4-methoxybenzyl.

SUMMARY OF THE INVENTION

The present invention provides a method for the hydrolysis of acarboxy-protected ester by reacting said ester with a compound selectedfrom the group consisting of the tetrahalogenides of titanium, tin andtellurium.

Especially, the process of the present invention can be appliedadvantageously for the hydrolysis of β-lactam esters of general formula(I) to give corresponding cephalosporin or penicillin derivatives offormula (II) as depicted in the scheme below. In particular, the estersare tert-butyl and 4-methoxy-benzyl esters. The Lewis acid is selectedfrom the group consisting of tellurium tetrahalogenide, tintetrahalogenide and titanium tetrahalogenide. ##STR1## with R₁ ishydrogen, hydroxy, amine, halogen or lower alkyl;

R₂ is an optionally substituted phenyl or phenoxy or 5- or 6-memberedheterocyclic ring;

R₃ is a carboxy-protecting group;

Z is oxygen, sulphur (optionally oxidized to sulfoxide or sulfone) orCHR₅ with R₅ is hydrogen or lower alkyl; and

Y is ##STR2## with R₄ is optionally substituted alkylidene; and

X₁ is hydrogen, halogen or (lower) alkoxy or optionally substitutedmethyl or alkoxycarbonyl.

According to another aspect of this invention, the novelcompound(6R,7R)-3-(2,4-dinitrostyryl)-7-phenylacetamido-ceph-3-em-4-carboxylicacid and salts and esters thereof, especially the E-isomer, has beenprovided for.

SPECIFIC EMBODIMENTS

According to the present invention, a process is provided fordeesterification of carboxylate esters, for instance resulting in thepreparation of 7-acylacetamido-cephem-4-carboxylic acids,7-acylacetamido-cepham-4-carboxylic acids or 6-amino-penicillanic acidand pharmaceutically acceptable salts thereof of formula (II), startingfrom the corresponding esters of formula (I). The deesterificationusually will be carried out in an organic solvent at a temperature ofabout -10°-20° C., preferably of about -5° C.-5° C.

The group R₁ can be optionally protected amino, halogen, hydrogen,optionally protected hydroxy or lower alkyl. Preferably R₁ is hydrogen.

The acylamido group R₂ can be any group hitherto disclosed, in thechemical literature and patent specifications or known to those skilledin the art of cephalosporin and penicillin chemistry. Preferably R₂ isone present in the 6β-side chain of penicillins that can be obtained byfermentative procedures. The latter penicillins can be converted intocephalosporins by known methods. Suitable groups represented by R₂ are,for example, phenoxyacetamido, phenylacetamido and 2-thienylacetamido.

The group R₃ can be any group known to those skilled in the art forprotecting the carboxy group of cephalosporanic acid or penicillanicacid derivatives. Preferably R₃ represents an ester group which can beeasily introduced. Particularly suitable ester groups are allyl,benzhydryl, benzyl, 2-bromoethyl, tert-butyl, 4-methoxybenzyl, methyl,4-nitrobenzyl and 2,2,2-tri-chloroethyl.

The group R₄ can be a C1-C6 alkylidene group like propenyl, optionallysubstituted by substituents like an acyl or heterocyclic group,optionally substituted by for instance halogen, hydroxy or nitro groups.

Examples of β-lactam derivatives that may be produced by the process ofthis invention are intermediates for antibiotics such as cefamandole,cefatrizine, cefdinir, cefixime, cefmenoxime, cefpodoxime, cefprozil,cefroxadine, ceftibuten, ceftiofur, ceftizoxime, ceftriaxone,cefuroxime, cefuzonam, loracarbef, moxalactam, and also active compoundssuch as said antibiotics. Furthermore, using the process of thisinvention, β-lactamase indicating compounds such as cefesone andnitrocefin can be prepared.

The starting materials used in the present invention are preparedaccording to methods published earlier. 3-Alkenyl substituted cephemderivatives can be prepared as described in European patent applications292,806 and 421,219, and German. patent 2,249,165. 3-Acetoxymethyl-,3-methyl- and 3-thiomethyl substituted cephem derivatives are preparedaccording to Recl. Trav. Chim. Pays-Bas 1993, 112, 66. 3-Methylenecepham derivatives are prepared according to U.S. Pat. No. 4,985,554.

Tert-butyl-(6R,7R)-3-(2,4-dinitrostyryl)-7-phenylacetamido-ceph-3-em-4-carboxylatecan be prepared by reacting the corresponding(2-halo)-3-halomethyl-3-cephem compound, viz. tert-butyl-(1S, 6R,7R)-(2-halo)-3-halomethyl-1-oxo-7-phenylacetamido-3-cephem-4-carboxylate,with a phosphine according to EP-B-0299587 followed by reduction usingphosphorous trichloride and condensation with 2,4-dinitrobenzaldehyde.

METHODS OF ANALYSIS

HPLC Column: Chrompack Microsphere C18, 3 μm (100×3.0 mm).

Solvent: 30% Acetonitrile and 1% tetrahydrofuran in 7 nM

potassium dihydrogenphosphate, pH 2.6.

Flow: 1.2 ml.min⁻¹.

Detection: 254 nm.

Retention: 7-phenylacetamido-3-deacetoxycephaloporanic acid (3.70 min);(6R, 7R)-7-phenylacetamido-3- (E)-1-propenyl!-ceph-3-em-4-carboxylicacid (8.02 min); (6R,7R)-7-phenyl-acetamido-3-(Z)-1-propenyl!-ceph-3-em-4-carboxylic acid (6.20 min).

IR Infrared spectra were recorded on a Pye Unicam PU9714.

MS Mass spectra were obtained with an AMD 402 mass spectrometer.

NMR ¹ H NMR spectra were recorded on a Bruker AM 360 MHz instrument.Purities were determined with ¹ H NMR spectroscopy using an internalreference.

TLC Thin layer chromatography was performed using Merck Kiesel-gel 60F₂₅₄ plates as stationary phase and ethylacetate/toluene/acetic acid4/3/2/1 as mobile phase.

EXAMPLE 1

Synthesis of (6R,7R)-3-methyl-7-phenylacetamido-ceph-3-em-4-carboxylicacid

A stirred solution of tert-butyl(6R,7R)-3-methyl-7-phenyl-acetamido-ceph-3-em-4-carboxylate (0.873 g,purity 89%, 2.0 mmol) in dichloromethane (50 ml) was cooled to -20° C.Titanium tetrachloride (0.88 ml, 7.9 mmol) was added in 1 min. Afterstirring for 2 h at 0° C., the suspension was mixed with a chilled 2Msolution of hydrochloric acid in water (40 ml). The organic phase wasseparated and water was added. The pH was adjusted to 7.0 with a 2Msolution of sodium hydroxide in water and the aqueous phase wasseparated and the pH was adjusted to 2.0 with a 2M solution ofhydrochloric acid in water. A white product precipitated which wasisolated and dried to give 0.49 g of(6R,7R)-3-methyl-7-phenylacetamido-ceph-3-em-4-carboxylic acid (purity94%, yield 69.4%).

IR (KBr): 3270 cm⁻¹, 1770 cm⁻¹, 1700 cm⁻¹, 1655 cm⁻¹, 1550 cm⁻¹.

¹ H NMR (DMSO-d₆ ; 360 MHz): δ=2.03 (s, 3 H), 3.35/3.54 (ABq, 2 H,J=16.7 Hz), 3.55/3.62 (ABq, 2 H), 5.05 (d, 1 H, J=5.0 Hz), 5.60 (dd, 1H), 7.3 (m, 5 H), 9.07 (d, 1 H, J=6.9 Hz) ppm.

EXAMPLE 2

Synthesis of(4R,6R,7R)-3-methylene-7-phenylacetamido-cepham-4-carboxylic acid

A stirred solution of tert-butyl (4R, 6R, 7R)-3-methylene-7-phenylacetamido-cepham-4-carboxylate (0.83 g, purity93.7%, 2.0 mmol) in dichloromethane (80 ml) was cooled to 0° C. Titaniumtetrachloride (0.66 ml, 6.0 mmol) was added in 1 min. After stirring for4 h at 0° C., the suspension was mixed with a chilled 2M solution ofhydrochloric acid in water (40 ml). The organic phase was separated andwashed with a 1M solution of hydrochloric acid in water (20 ml), water(20 ml), and brine (20 ml). The organic phase was dried over magnesiumsulphate and evaporated to give 0.40 g of(4R,6R,7R)-3-methylene-7-phenylacetamido-cepham-4-carboxylic acid(purity 75%, yield 45.1%).

IR (KBr): 3280 cm⁻¹, 1745 cm⁻¹, 1635 cm⁻¹.

¹ H NMR (CDCl₃ ; 360 MHz): δ=3.17 (d, 1 H, J=15.0 Hz), 3.56/3.68 (m, 3H), 5.07 (s, 1 H), 5.23 (ABq, 2H, J=12.5 Hz), 5.64 (dd, 1 H), 6.29 (d,1H, J=11.0 Hz), 7.3 (m, 5 H).

EXAMPLE 3

Synthesis of (4R,6R,7R)-3-methyl-7-phenylacetamido-ceph-2-em-4carboxylic acid

A stirred solution of tert-butyl(4R,6R,7R)-3-methyl-7-phenylacetamido-ceph-2-em-4-carboxylate (0.776 g,2.0 mmol) in dichloromethane (30 ml) was cooled to 0° C. Titaniumtetrachloride (0.6 ml, 5.5 mmol) was added in 1 min. After stirring for2.5 h at 0° C., the suspension was mixed with a chilled 2M solution ofhydrochloric acid in water (40 ml). The organic-phase was separated andwashed with a 1M solution of hydrochloric acid in water (20 ml), water(20 ml), and brine (20 ml). The organic phase was concentrated to give0.55 g of (4R,6R,7R)-3-methyl-7-phenylacetamido-ceph-2-em-4-carboxylicacid (yield 82.7%).

EXAMPLE 4

Synthesis of (6R, 7R)-3-methyl-7-phenoxyacetamido-ceph-3-em-4-carboxylicacid

A stirred solution of tert-butyl(6R,7R)-3-methyl-7-phenoxyacetamido-ceph-3-em-4-carboxylate (0.41 g, 1.0mmol) in dichloromethane (25 ml) was cooled to 0° C. Titaniumtetrachloride (0.38 ml, 3.5 mmol) was added in 1 min. A yellowprecipitate was formed which was stirred for 2 h at 0°C. To thesuspension was added a chilled 1M solution of hydrochloric acid in.water (40 ml). The organic phase was separated, washed with water andbrine, dried over magnesium sulphate, and evaporated to give 0.30 g of(6R, 7R) -3-methyl-7-phenoxyacetamidoceph-3-em-4-carboxylic acid (purity63%, yield 54.3%).

IR (KBr): 3375 cm⁻¹, 1755 cm⁻¹, 1740 cm⁻¹, 1655 cm⁻¹.

¹ H NMR (DMSO-d₆ ; 360 MHz): δ=2.06 (s, 3 H), 3.42/3.47 (ABq, 2 H, J=8.3Hz), 3.59/3.64 (ABq, 2 H, J=16.6 Hz), 5.08 (d, 1 H), 5.66 (dd, 1 H), 6.3(m, 5 H), 9.02 (d, 1 H, J=9.9 Hz) ppm.

EXAMPLE 5

Synthesis of(6R,7R)-7-phenylacetamido-3-(1-propenyl)-ceph-3-em-4-carboxylic acid,Z-isomer

A stirred solution of 4-methoxybenzyl (6R,7R)-7-phenylacet-amido-3-(1-propenyl)-ceph-3-em-4-carboxylate (0.509 g,purity 9% E-isomer, 84% Z-isomer, 0.99 mmol) in dichloromethane (15 ml)was cooled to 2° C. Titanium tetrachloride (0.5 ml, 4.5 mmol) was addedin 1 min. After 30 min the brown suspension was mixed with a chilledmixture of dichloromethane (50 ml) and a 2M solution of hydrochloricacid in water (50 ml). The organic phase was separated and extractedwith a 2M solution of hydrochloric acid in water (3×50 ml). The aqueousphases were extracted with dichloromethane (25 ml). The combined organicphases were analyzed using HPLC: 0.036 g (6R,7R)-7-phenylacetamido-3-(E)-1-propenyl!-ceph-3-em-4-carboxylic acid (0.10 mmol, yield 10.2%);0.301 g (6R,7R)-7-phenylacetamido-3-(Z)-1-propenyl!-ceph-3-em-4-carboxylic acid (0.84 mmol, yield 84.8%).The overall yield is therefore 95.0%.

EXAMPLE 6

Screening of lewis acids in the hydrolysis of tert-butyl(6R,7R)-7-phenyl-acetamido-3-(1-propenyl)-ceph-3-em-4-carboxylate

To a stirred solution of tert-butyl(6R,7R)-7-phenylacet-amido-3-(1-propenyl)-ceph-3-em-4-carboxylate indichloromethane (30 ml.g⁻¹) was added Lewis acid (3-5 equiv., see tablefor conditions). The formation of(6R,7R)-7-phenylacetamido-3-(1-propenyl)-ceph-3-em-4-carboxylic acid wasmonitored either by HPLC or TLC. The results are summarized in thetable.

    ______________________________________    Lewis T      Time   Yield    acid  (° C.)                 (h)    (%)  Remarks    ______________________________________    AlCl.sub.3          25     28     50   According to TLC; some degradation                             observed.    BCl.sub.3          -10    4      20   According to TLC; extensive                             degradation observed.    BF.sub.3          25     18     0    According to TLC; no product, no                             starting material.    FeCl.sub.3          5      2.5    34   According to HPLC; yield after work-                             up.    SiCl.sub.4          25     72     0    According to TLC; no reaction                             observed.    SnCl.sub.4          -10    2.5    88   According to HPLC; tin-residues are                             difficult to remove during work-up.    TiCl.sub.4          5      3      91   According to HPLC.    ______________________________________

EXAMPLE 7

Synthesis of(1S,6R,7R)-3-acetoxymethyl-1-oxo-7-phenylacetamido-ceph-3-em-4-carboxylicacid

To a stirred solution of tert-butyl(1S,6R,7R)-3-acetoxy-methyl-1-oxo-7-phenylacetamido-ceph-3-em-4-carboxylate(0.23 g, purity 89.3%, 0.423 mmol) in acetonitrile (2.5 ml) was added asolution of tellurium tetrachloride (0.135 g, 0.5 mmol) in acetonitrile(2.5 ml). After stirring for 1 h at 23° C., the crystalline precipitatewas collected by filtration, washed with acetonitrile (0.5 ml) and driedover phosphorous pentachloride under vacuum to give 0.147 g of(1S,6R,7R)-3-acetoxymethyl-1-oxo-7-phenylacetamido-ceph-3-em-4-carboxylicacid (purity 87%, 75.1% yield). The filtrate was treated with ether (10ml) to give a second crop of product (0.008 g, purity 82%, 3.9% yield).The total yield is 79.0%.

EXAMPLE 8

Synthesis of(6R,7R)-7-phenylacetamido-3-(1-propenyl)-ceph-3-em-4-carboxylic acid,Z-isomer

At 0° C., titanium tetrachloride (420 ml, 3.82 mol) was added in 30 minto a solution of tert-butyl (6R,7R)-7-phenylacetamido-3-(1-propenyl)-ceph-3-em-4-carboxylate, (404.8 g,976.5 mmol; ratio E-isomer: Z-isomer=0.05). After stirring for 1 h at1±1° C., the solution is transferred to a stirred 2M solution ofhydrochloric acid in water (6.00 l). The layers are separated and theaqueous phase was back-extracted with dichloromethane (800 ml). Thecombined organic phases were extracted with a 2M solution ofhydrochloric acid in water (3×31) and each batch of water wasback-extracted with the wash-dichloromethane. The combined organicphases (6.03 l) were analyzed using HPLC: 16.9g(6R,7R)-7-phenylacetamido-3- (E)-1-propenyl!-ceph-3-em-4-carboxylicacid (47.2 mmol, yield 4.8%); 296.1 g (6R,7R)-7-phenylacetamido-3-(Z)-1-propenyl!-ceph-3-em-4-carboxylicacid (826.1 mmol, yield 84.6%).The overall yield is therefore 89.4%.

EXAMPLE 9

Synthesis of(6R,7R)-3-(2,4-dinitrostyryl)-7-phenylacetamido-ceph-3-em-4-carboxylicacid, E-isomer

A stirred solution of tert-butyl(6R,7R)-3-(2,4-dinitro-styryl)-7-phenylacetamido-ceph-3-em-4-carboxylate(67.41 g, purity 8% E-isomer, 81% Z-isomer, 105.9 mmol) indichloro-methane (1685 ml) was cooled to -25° C. Titanium tetrachloride(53 ml, 482 mmol) was added in 10 min and the temperature was brought to0° C. After 105 min a chilled 2M solution of hydrochloric acid in waterwas added at such a rate that the temperature remained under 10° C. Theorganic phase was separated and extracted with a 2M solution ofhydrochloric acid in water (2×1685 ml) and brine (1685 ml). The organicphase was concentrated under reduced pressure to give an orange foam.Crude product thus obtained was crystallized by dissolving in acetone(1350 ml) at 65° C. and adding water (675 ml). Crystallization wasallowed to proceed for 16 h at 0° C. and the crystals were collected byfiltration. Recrystallization of the product was performed by dissolvingthe material in acetone/acetic acid (2:1) at 53° C., removing solvent(1700 ml) by evaporation under reduced pressure and stirring for 16 h at20° C. Crystals were collected by filtration, washed with acetic acid(300 ml) and ether (250 ml), and dried under vacuum at 45° C. to give34.33 g (purity 99% E-isomer, 66.6 mmol; yield 63%) of(6B,7R)-3-(2,4-dinitrostyryl)-7-phenylacetamido-ceph-3-em-4-carboxylicacid as yellow crystals.

IR (KBr): 3300 cm⁻¹, 1780 cm⁻¹, 1715 cm⁻¹, 1625 cm⁻¹, 1525 cm⁻¹.

MS (DCI): m/z=528.0 (MNH₄ ⁺).

¹ H NMR (CDCl₃ /DMSO-d₆, 1:2; 360 MHz): δ=3.50/3.58 (ABq, 2 H. J=14.1Hz), 3.62/3.77 (ABq, 2 H, J=17.5 Hz), 5.05 (d, 1 H, J=4.9 Hz), 5.72 (dd,1 H, J₆,7 =4.9 Hz, J₇,NH =8.3 Hz), 7.3 (m, 6 H), 7.63 (d, 1 H, J=16.1Hz), 7.82 (d, 1 H, J=8.8 Hz), 8.33 (dd, 1 H, J₁ =2.1 Hz, J₂ =8.8 Hz),8.66 (d, 1 H, J=2.1 Hz), 8.97 (d, 1 H, J=8.3 Hz) ppm.

EXAMPLE 10

Synthesis of (6R,7R) -7-phenylacetamido-3-(1-phenyl-1-H-tetrazol-5-yl)thiomethyl-ceph-3-em-4-carboxylic acid

A stirred solution of tert-butyl (6R, 7R)-7-phenylacetamido-3-(1-phenyl-1-H-tetrazol-5-yl),thiomethyl-ceph-3-em-4-carboxylate(1.0 g, purity 80%, 1.42 mmol) in dichloromethane (50 ml) was cooled to0°C. Titanium tetrachloride (0.62 ml, 5.6 mmol) was added in 1 min.After stirring for 1 h at 0° C., the suspension was mixed with a chilled2M solution of hydrochloric acid in water (40 ml). The organic phase wasseparated and washed with a 1M solution of hydrochloric acid in water(20 ml), water (20 ml), and brine (20 ml). The organic phase was driedover magnesium sulphate and evaporated to give 0.55 g of(6R,7R)-7-phenylacetamido-3-(1-phenyl-1-H-tetrazol-5-yl)thiomethyl-ceph-3-em-4-carboxylic acid (purity 60%, yield 45.8%).

IR (KBr): 3260 cm⁻¹, 1770 cm⁻¹, 1485 cm⁻¹.

¹ H NMR (DMSO-d₆ ; 360 MHz): δ=1.25 (s, 2H), 3.47/3.65 (m, 2 H), 3.68(ABq, 2H, J=11.7 Hz), 4.28 (d, 1H, J=13.3 Hz), 4.56 (d, 1H, J=13.3 Hz),5.04 (d, 2H, J=6.1 Hz), 5.71 (m, 2H), 7.01 (m, 1H), 7.2/7.8 (m, 10 H),9.14 (d, 1H, J=11.5 Hz).

EXAMPLE 11

Synthesis of(6R,7R)-7-phenylacetamido-3-(1-phenyl-1-H-tetrazol-5-yl)thiomethyl-ceph-3-em-4-carboxylicacid

A stirred solution of tert-butyl(6R,7R)-7-phenylacetamido-3-(1-phenyl-1-H-tetrazol-5-yl)thiomethyl-ceph-3-em-4-carboxylate (1.0 g, purity 80%, 1.42 mmol) indichloromethane (50 ml) and anisole (0.93 ml) was cooled to 0° C.Titanium tetrachloride (0.62 ml, 5.6 mol) was added in 1 min. Afterstirring for 2.5 h at 0° C., the suspension was mixed with a chilled 2Msolution of hydrochloric acid in water (40 ml). The organic phase wasseparated and washed with a 1M solution of hydrochloric acid in water(20 ml), water (20 ml), and brine (20 ml). The organic phase was driedover magnesium sulphate and evaporated to give 0.60 g of (6R,7R)-7-phenylacetamido-3-(1-phenyl-1-H-tetrazol-5-yl)thiomethyl-ceph-3-em-4-carboxylicacid (purity 60%, yield 49.9%).

IR (KBr): 3260 cm⁻¹, 1770 cm⁻¹, 1485 cm⁻¹.

¹ H NMR (DMSO-d₆ ; 360 MHz): δ=1.25 (s, 2H), 3.47/3.65 (m, 2 H),, 3.68(ABq, 2H, J=11.7 Hz), 4.28 (d, 1H, J=13.3 Hz), 4.56 (d, 1H, J=13.3 Hz),5.04 (d, 2H, J=6.1 Hz), 5.71 (m, 2H), 7.01 (m, 1H), 7.2/7.8 (m, 10 H),9.14 (d, 1H, J=11.5 Hz).

EXAMPLE 12

Synthesis of(6R,7R)-7-phenylacetamido-3-(1-phenyl-1-H-tetrazol-5-yl)thiomethyl-ceph-3-em-4-carboxylicacid

A stirred solution of tert-butyl (6R,7R)-7-phenylacetamido-3-(1-phenyl-1-H-tetrazol-5-yl)thiomethyl-ceph-3-em-4-carboxylate (5.0 g, purity 80%, 7.09 mmol) indichloromethane (150 ml) was cooled to 0° C. A solution of titaniumtetrachloride (2.33 ml, 21.2 mmol) in dichloromethane (15 ml) was added.After stirring for 4.5 h at 0° C., the suspension was mixed with achilled 2M solution of hydrochloric acid in water. The organic phase wasseparated and washed with a 1M solution of hydrochloric acid in water,water, and brine. The organic phase was dried over magnesium sulphateand concentrated to give 3.55 g of(6R,7R)-7-phenylacetamido-3-(1-phenyl-1-H-tetrazol-5-yl)thiomethyl-ceph-3-em-4-carboxylicacid (purity 60%, yield 59.1%).

IR (KBr): 3260 cm⁻¹, 1770 cm⁻¹, 1485 cm⁻¹.

¹ H NMR (DMSO-d₆ ; 360 MHz): δ=1.25 (s, 2H), 3.47/3.65 (m, 2 H), 3.68(ABq, 2H, J=11.7 Hz), 4.28 (d, 1H, J=13.3 Hz), 4.56 (d, 1H, J=13.3 Hz),5.04 (d, 2H, J=6.1 Hz), 5.71 (m, 2H), 7.01 (m, 1H), 7.2/7.8 (m, 10 H),9.14 (d, 1H, J=11.5 Hz).

EXAMPLE 13

Synthesis of (6R,7R)-7-phenylacetamido-3-(pyrimidin-2-yl)thiomethyl-ceph-3-em-4-carboxylicacid

A stirred solution of tert-butyl (6R,7R)-7-phenylacetamido-3-(pyrimidin-2-yl)thiomethyl-ceph-3-em-4-carboxylate(3.5 g, purity 53%, 3.71 mmol) in dichloromethane (150 ml) and anisole(4.65 ml) was cooled to 0° C. A solution of titanium tetrachloride (2.3ml, 21 mmol) in dichloromethane (10 ml) was added. After stirring for3.5 h at 0° C., the suspension was mixed with a chilled 2M solution ofhydrochloric acid in water. The organic phase was separated and washedwith a 1M solution of hydrochloric acid in water, water, and brine. Theorganic phase was dried over magnesium sulphate and concentrated to give2.10 g of(6R,7R)-7-phenylacetamido-3-(pyrimidin-2-yl)thio-methyl-ceph-3-em-4-carboxylicacid (purity 75%, yield 50.9%).

IR (KBr): 3240 cm⁻¹, 1760 cm⁻¹, 1695 cm⁻¹, 1640 cm⁻, 1525 cm⁻¹.

¹ H NMR (DMSO-d₆ ; 360 MHz): δ=2.52 (s, 1H), 3.47/3.64 (ABq, 2 H, J=12.5Hz), 3.75/4.02 (m, 2H), 4.60 (d, 1H, J=15.0 Hz), 5.08 (d, b 1H, J=5.0Hz), 5.62 (ABq, 1H, J=5.0 Hz), 7.28 (m, 6H), 8.68 (d, 2H, J=3.4 Hz),9.15 (d, 1H, J=10.0 Hz).

We claim:
 1. Process for the hydrolysis of a tert-butylester,characterized by reacting said ester with a compound selected from thegroup consisting of the tetrahalogenides of titanium, tin and tellurium.2. A process according to claim 1, characterized by the hydrolysis of aβ-lactam ester of formula (I) ##STR3## with R₁ is hydrogen, hydroxy,amine, halogen or lower alkyl;R₂ is an optionally substituted phenyl orphenoxy or 5- or 6-membered heterocyclic ring; R₃ is a t-butyl group; Zis oxygen, sulphur (optionally oxidized to sulfoxide or sulfone) or CHR₅with R₅ is hydrogen or lower alkyl; and Y is ##STR4## with R₄ isoptionally substituted alkylidene; andX₁ is hydrogen, halogen or (lower)alkoxy or optionally substituted methyl or alkoxycarbonyl.
 3. A processaccording to claim 1 characterized by the application of a compoundselected from the group titanium tetrachloride, tin tetrachloride andtellurium tetrachloride. 4.(6R,7R)-3-(2,4-dinitrostyryl)-7-phenylacetamido-ceph-3-em-4-carboxylicacid and salts and esters thereof.
 5. The E-isomer of(6R,7R)-3-(2,4-dinitrostyryl)-7-phenyl-acetamido-ceph-3-em-4-carboxylicacid and of salts and esters thereof.